The matrix metalloproteinases (MMP""s) are a family of zinc containing endopeptidases which are capable of cleaving large biomolecules such as the collagens, proteoglycans and gelatins. Expression is upregulated by pro-inflammatory cytokines and/or growth factors. The MMP""s are secreted as inactive zymogens which, upon activation, are subject to control by endogenous inhibitors, for example, tissue inhibitor of metalloproteinases (TIMP) and xcex12-macroglobulin. Chapman, K. T. et al., J. Med. Chem. 36, 4293-4301 (1993); Beckett, R. P. et al., DDT 1, 16-26 (1996). The characterizing feature of diseases involving the enzymes appears to be a stoichiometric imbalance between active enzymes and endogenous inhibitors, leading to excessive tissue disruption, and often degradation. McCachren, S. S., Arthritis Rheum. 34, 1085-1093 (1991).
The discovery of different families of matrix metalloproteinase, their relationships, and their individual characteristics have been categorized in several reports. Emonard, H. et al., Cell Molec. Biol. 36, 131-153 (1990); Birkedal-Hansen, H., J. Oral Pathol. 17, 445-451 (1988); Matrisian, L. M., Trends Genet. 6, 121-125 (1990); Murphy, G. J. P. et al., FEBS Lett. 289, 4-7 (1991); Matrisian, L. M., Bioessays 14, 455-463 (1992). Three groups of MMPs have been delineated: the collagenases which have triple helical interstitial collagen as a substrate, the gelatinases which are proteinases of denatured collagen and Type IV collagen, and the stromelysins which were originally characterized as proteoglycanases but have now been identified to have a broader proteolytic spectrum. Examples of specific collagenases include fibroblast collagenase characterized as proteoglycanases but have now been identified to have a broader proteolytic spectrum. Examples of specific collagenases include fibroblast collagenase (MMP-1), neutrophil collagenase (MMP-8), and collagenase 3 (MMP-13). Examples of gelatinases include 72 kDa gelatinase (gelatinase A; MMP-2) and 92 kDa gelatinase (gelatinase B; MMP-9). Examples of stromelysins include stromelysin 1 (MMP-3), stromelysin 2 (MMP-10) and matrilysin (MMP-7). Other MMPs which do not fit neatly into the above groups include metalloelastase (MMP-12), membrane-type MMP (MT-MMP or MMP-14) and stromelysin 3 (MMP-11). Beckett, R. P. et al., supra.
Over-expression and activation of MMPs have been linked with a wide range of diseases such as cancer; rheumatoid arthritis; osteoarthritis; chronic inflammatory disorders, such as emphysema; cardiovascular disorders, such as atherosclerosis; corneal ulceration; dental diseases such as gingivitis and periodontal disease; neurological disorders, such as multiple sclerosis; and smoking-induced emphysema.
For example, in adenocarcinoma, invasive proximal gastric cells express the 72 kDa form of collagenase Type IV, whereas the noninvasive cells do not. Schwartz, G. K. et al., Cancer 73, 22-27 (1994). Rat embryo cells transformed by the Ha-ras and v-myc oncogenes or by Ha-ras alone are metastatic in nude mice and release the 92 kDa gelatinase/collagenase (MMP-9). Bernhard, E. J. et al., Proc. Natl. Acad. Sci. 91, 4293-4597 (1994). The plasma concentration of MMP-9 was significantly increased (P less than 0.01) in 122 patients with gastrointestinal tract cancer and breast cancer. Zucker, S. et al., Cancer Res. 53, 140-146 (1993). Moreover, intraperitoneal administration of batimastat, a synthetic MMP inhibitor, gave significant inhibition in the growth and metastatic spread and number of lung colonies which were produced by intravenous injection of the B16-BL6 murine melanoma in C57BL/6N mice. Chirivi, R. G. S. et al., Int. J. Cancer 58, 460-464 (1994). Over-expression of TIMP-2, the endogenous tissue inhibitor of MMP-2, markedly reduced melanoma growth in the skin of immunodeficient mice. Montgomery, A. M. P. et al., Cancer Res. 54, 5467-5473 (1994).
Accelerated breakdown of the extracellular matrix of articular cartilage is a key feature in the pathology of both rheumatoid arthritis and osteoarthritis. Current evidence suggests that the inappropriate synthesis of MMPs is the key event. Beeley, N. R. A. et al., Curr. Opin. Ther. Patents, 4(1), 7-16 (1994). The advent of reliable diagnostic tools have allowed a number of research groups to recognize that stromelysin is a key enzyme in both arthritis and joint trauma. Beeley, N. R. A. et al., Id.; Hasty, K. A. et al., Arthr. Rheum. 33, 388-397 (1990). It has also been shown that stromelysin is important for the conversion of procollagenase to active collagenase. Murphy, G. et al., Biochem. J. 248, 265-268 (1987).
Furthermore, a range of MMPs can hydrolyse the membrane-bound precursor of the pro-inflammatory cytokine tumor necrosis factor xcex1 (TNF-xcex1). Gearing, A. J. H. et al., Nature 370, 555-557 (1994). This cleavage yields mature soluble TNF-xcex1 and the inhibitors of MMPs can block production of TNF-xcex1 both in vitro and in vivo. Gearing, A. J. H. et al., Id.; Mohler, K. M. et al., Nature 370, 218-220 (1994); McGeehan, G. M. et al., Nature 370, 558-561 (1994). This pharmacological action is a probable contributor to the antiarthritic action of this class of compounds seen in animal models. Beckett, R. P. et al., supra.
Stromelysin has been observed to degrade the xcex11-proteinase inhibitor which regulates the activity of enzymes such as elastase, excesses of which have been linked to chronic inflammatory disorders such as emphysema and chronic bronchitis. Inhibition of the appropriate MMP may thus potentiate the inhibitory activity of endogenous inhibitors of this type. Beeley, N. R. A. et al., supra.; Wahl, R. C. et al., Annual Reports in Medicinal Chemistry 25, 177-184 (1990).
High levels of mRNA corresponding to stromelysin have been observed in atherosclerotic plaques removed from heart transplant patients. Henney, A. M., et al., Proc. Natl. Acad. Sci. 88, 8154-8158 (1991). It is submitted that the role of stromelysin in such plaques is to encourage rupture of the connective tissue matrix which encloses the plaque. This rupture is in turn thought to be a key event in the cascade which leads to clot formation of the type seen in coronary thrombosis. MMP inhibition is thus a preventive measure for such thromboses.
Collagenase, stromelysin and gelatinase have been implicated in the destruction of the extracellular matrix of the cornea. This is thought to be an important mechanism of morbidity and visual loss in a number of ulcerative ocular diseases, particularly those following infection or chemical damage. Burns, F. R. et al., Invest. Opthalmol. and Visual Sci. 32, 1569-1575 (1989). The MMPs present in the eye during ulceration are derived either endogenously from infiltrating leucocytes or fibroblasts, or exogenously from microbes.
Collagenase and stromelysin activities have been identified in fibroblasts isolated from inflamed gingiva and the levels of enzyme have been correlated with the severity of the gingivitis observed. Beeley, N. R. A. et al., supra.; Overall, C. M. et al., J. Periodontal Res. 22, 81-88 (1987).
Excessive levels of gelatinase-B in cerebrospinal fluid has been linked with incidence of multiple sclerosis and other neurological disorders. Beeley, N. R. A. et al., supra.; Miyazaki, K. et al., Nature 362, 839-841 (1993). The enzyme may play a key role in the demyelination of neurones and the breakdown of the blood brain barrier which occurs in such disorders.
In addition, a recent study indicates that MMP-12 is required for the development of cigarette smoke-induced emphysema in mice. Science, 277, 2002 (1997).
Apart from the role of these potentially very destructive enzymes in pathology, the MMPs play an essential role in cell regrowth and turnover in healthy tissue. Broad spectrum inhibition of the MMPs in the clinical setting results in musculoskeletal stiffness and pain. H. S. Rasmussen and P. P. McCann, Pharmacol. Ther., 75, 69-75 (1997). This side effect and others associated with broad spectrum inhibition may be enhanced in chronic administration. Thus, it would be advantageous to provide selective MMP inhibitors.
While the 1-carboxymethyl-2-oxo-azepan derivatives of the present application are useful for inhibition of MMP-1, MMP-2, and MMP-3 they are selective inhibitors of MMP-12. Because they are selective, the compounds of the present application are expect to be useful for long term therapy with less of the complications related to broad spectrum inhibition. Thus, while the compounds of the present application are useful for the treatment of a variety of MMP mediated diseases and conditions, these selective inhibitors are particularly useful for the treatment of smoking-induced emphysema.
The present invention provides novel compounds of the formula 
wherein
R1 is selected from a group consisting of hydrogen, C1-C6 alkyl, xe2x80x94CH2SCH2NHCOCH3, xe2x80x94(CH2)pxe2x80x94A, xe2x80x94(CH2)mxe2x80x94B, and xe2x80x94CH2xe2x80x94Dxe2x80x94R7;
wherein
A is selected from a group consisting of C6-C10 aryl, C3-C9 heteroaryl, or cyclohexyl;
B is selected from a group consisting of xe2x80x94N(R7)2, guanidino, nitroguanidino, xe2x80x94C(O)OR6 and xe2x80x94C(O)NR6;
D is selected from a group consisting of oxy and thio;
R2 is selected from a group consisting of C1-C4 alkyl, xe2x80x94(CH2)pxe2x80x94(C3-C9) heteroaryl, and xe2x80x94(CH2)pxe2x80x94Ar1;
wherein
Ar1 is selected from the group consisting of phenyl and naphthyl optionally substituted with a substituent selected from the group consisting of halogen, C1-C4 alkyl, xe2x80x94OR6, xe2x80x94N(R6)2, xe2x80x94SO2N(R6)2 and xe2x80x94NO2;
R3 is selected from a group consisting of C1-C6 alkyl, Wxe2x80x94(CH2)mxe2x80x94, and Qxe2x80x94Zxe2x80x94(CH2)mxe2x80x94;
wherein
W is phthalimido;
Z is selected from the group consisting of a bond, xe2x80x94Oxe2x80x94, xe2x80x94NR6xe2x80x94, xe2x80x94C(O)NR6xe2x80x94, xe2x80x94NR6C(O)xe2x80x94, xe2x80x94NHC(O)NR6xe2x80x94, xe2x80x94OC(O)NR6xe2x80x94, xe2x80x94HNC(O)Oxe2x80x94, and xe2x80x94SO2NR6xe2x80x94;
Q is selected from the group consisting of hydrogen, and Yxe2x80x94(CH2)nxe2x80x94;
wherein
Y is selected from the group consisting of hydrogen, C6-C10 aryl, C3-C9 heteroaryl, xe2x80x94C(O)OR6, xe2x80x94N(R6)2, morpholino, piperidino, pyrrolidino, and isoindolyl;
R4 is selected from a group consisting of hydrogen, xe2x80x94C(O)R7, xe2x80x94C(O)xe2x80x94(CH2)qxe2x80x94K and xe2x80x94Sxe2x80x94G;
wherein
K is selected from the group consisting of 
G is selected from the group consisting of 
R6 is selected from the group consisting of hydrogen and C1-C6 alkyl;
R7 is selected from the group consisting of hydrogen, C1-C4 alkyl, and xe2x80x94(CH2)pxe2x80x94Ar2;
wherein
Ar2 is selected from the group consisting of phenyl and naphthyl optionally substituted with a substituent selected from the group consisting of halogen, C1-C4 alkyl, xe2x80x94OR6, xe2x80x94N(R6)2, xe2x80x94SO2N(R6)2 and xe2x80x94NO2;
R9 and R10 are each independently selected from the group consisting of C1-C4 alkyl and xe2x80x94(CH2)pxe2x80x94Ar2;
R11 is selected from the group consisting of xe2x80x94CF3, C1-C10 alkyl and xe2x80x94(CH2)pxe2x80x94Ar2;
R12 is selected from the group consisting of hydrogen, C1-C6 alkyl, xe2x80x94CH2CH2S(O)pCH3, and arylalkyl;
R13 is selected from the group consisting of hydrogen, hydroxy, amino, C1-C6 alkyl, N-methylamino, N,N-dimethylamino, xe2x80x94CO2R17 and xe2x80x94OC(O)R18;
wherein
R17 is selected from the group consisting of hydrogen, xe2x80x94C(O)C(CH3)3, C1-C4 alkyl, xe2x80x94(CH2)pxe2x80x94Ar2, and diphenylmethyl;
R18 is hydrogen, C1-C6 alkyl and phenyl;
R14 is selected from the group consisting of 1 or 2 substituents independently chosen from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, and halogen;
R15 is selected from the group consisting of hydrogen, C1-C6 alkyl and xe2x80x94(CH2)pxe2x80x94Ar2;
R16 is selected from the group consisting of hydrogen and C1-C4 alkyl;
V1 is selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, and xe2x80x94NHxe2x80x94;
V2 is selected from the group consisting of xe2x80x94Nxe2x80x94 and xe2x80x94CHxe2x80x94;
V3 is selected from the group consisting of a bond and xe2x80x94C(O)xe2x80x94;
V4 is selected from the group consisting of xe2x80x94(CH2)wxe2x80x2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR7xe2x80x94, and xe2x80x94NC(O)R11xe2x80x94;
Xxe2x80x2 is selected from the group consisting of xe2x80x94CHxe2x80x94 and xe2x80x94Nxe2x80x94;
m is an integer from 2-4;
n is an integer from 0-4;
p is an integer from 0-2;
t is an integer from 1-2;
w is an integer from 1-3;
wxe2x80x2 is an integer from 0-1;
or a pharmaceutically acceptable salt, stereoisomer or hydrate thereof.
The present invention further provides a method of inhibiting matrix metallo-proteinases (MMPS) in a patient in need thereof comprising administering to the patient an effective matrix metalloproteinase inhibiting amount of a compound of formnula (1).
In addition, the present invention provides a composition comprising an assayable amount of a compound of formula (1) in admixture or otherwise in association with an inert carrier. The present invention also provides a pharmaceutical composition comprising an effective MMP inhibitory amount of a compound of formula (1) in admixture or otherwise in association with one or more pharmaceutically acceptable carriers or excipients.
As used in this application:
a) the designation xe2x80x9cxe2x80x9d refers to a bond for which the stereochemistry is not designated.
b) the designation xe2x80x9cxe2x80x9d refers to a bond that protrudes forward out of the plane of the page.
c) the designation xe2x80x9cxe2x80x9d refers to a bond that protrudes backward out of the plane of the page.
d) the term xe2x80x9cC1-C4 alkylxe2x80x9d refers to a saturated straight or branched chain hydrocarbyl radical of one to four carbon atoms and includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tertiary butyl and the like.
e) the term xe2x80x9cC1-C6 alkylxe2x80x9d refers to a saturated straight or branched chain hydrocarbyl radical of one to six carbon atoms and includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, n-pentyl, sec-pentyl, isopentyl, n-hexyl and the like.
f) the term xe2x80x9cC1-C10 alkylxe2x80x9d refers to a saturated straight or branched chain hydrocarbyl radical of one to ten carbon atoms and includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, n-pentyl, sec-pentyl, isopentyl, n-hexyl, 2,3-dimethyl-2-butyl, heptyl, 2,2-dimethyl-3-pentyl, 2-methyl-2-hexyl, octyl, 4-methyl-3-heptyl, nonyl, decyl and the like.
g) the term xe2x80x9cC1-C4 alkoxyxe2x80x9d refers to a straight or branched alkoxy group containing from 1 to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, and the like.
h) the designation xe2x80x9cxe2x80x94C(O)xe2x80x94xe2x80x9d refers to a carbonyl group of the formula 
i) the term xe2x80x9cC6-C10 arylxe2x80x9d refers to a cyclic aromatic assemblage of conjugated carbon atoms, optionally substituted with one to three substituents selected from the group consisting of F, Cl, C1-C4 alkyl, xe2x80x94OR7, xe2x80x94N(R6)2, or xe2x80x94NO2, including phenyl, 1-naphthyl, 2-naphthyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hyroxyphenyl, 2,3-dihydroxyphenyl, 2,4-dihydroxyphenyl, 3,4-dihydroxyphenyl, 2,3,4-trihydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2,3,4-trichlorophenyl, 4-bromophenyl, 3,4-dibromophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3-tolyl, 4-tolyl, 4-ethylphenyl, 4-isopropylphenyl, 3-aminophenyl, 4-aminophenyl, 3,4-diaminophenyl, N-methyl-4-aminophenyl, 2-nitrophenyl, 4-nitrophenyl, 3-bromo-4-tolyl, and the like.
j) the term xe2x80x9cC3-C9 heteroarylxe2x80x9d means a cyclic or bicyclic, aromatic assemblage of conjugated carbon atoms and from 1 to 3 nitrogen, oxygen and sulfur atoms, for example, pyridinyl, 2-quinoxalinyl, quinolinyl, pyridazinyl, pyrimidyl, pyrazolyl, pyrazyl, thiophyl, furyl, imidazolyl, oxazolyl, thiazolyl, benzimidazolyl and the like.
k) the terms xe2x80x9cPhtNxe2x80x9d or xe2x80x9cphthalimidoxe2x80x9d refer to a phthalimido (1,3-dihydro-1,3-dioxo-(2H)xe2x80x94isoindolyl) functionality of the formula: 
l) the designations xe2x80x9cC(O)NR6xe2x80x9d, xe2x80x9cNR6C(O)xe2x80x9d, xe2x80x9cNHC(O)NR6xe2x80x9d, xe2x80x9cOC(O)NR6xe2x80x9d, xe2x80x9cR6NC(O)Oxe2x80x9d or xe2x80x9cSO2NR6xe2x80x9d refer to amide bond or modified amide bond functionalities and are represented, respectively, by the following formulae: 
m) the terms xe2x80x9cAr1xe2x80x9d, xe2x80x9cAr2xe2x80x9d or xe2x80x9carylxe2x80x9d refers to a phenyl or naphthyl group unsubstituted or substituted with from one to three substituents selected from the group consisting of F, Cl, C1-C4 alkyl, xe2x80x94OR7, xe2x80x94N(R6)2, SO2N(R6)2 or xe2x80x94NO2; specifically included within the scope of the term xe2x80x9caralkylxe2x80x9d are phenyl, naphthyl, naphthylmethyl, phenylmethyl or benzyl, phenylethyl, p-methoxybenzyl, 3,4-methylenedioxybenzyl, p-fluorobenzyl and p-chlorobenzyl.
For the purposes of this invention, when xe2x80x9cAr1xe2x80x9d is phenyl, shown below, 
the radical is attached in the 1-position and the substituent or substituents may only be attached at the 3, 4 or 5 positions of the phenyl moiety.
When xe2x80x9cAr1xe2x80x9d is naphthyl, shown below, 
the radical can be attached at the 2-position, and the substituent or substituents may only be attached at the 5, 6, 7 or 8 positions.
For the purposes of this invention, when xe2x80x9cAr2xe2x80x9d is phenyl, the substituent or substituents can be attached at the 2, 3, 4, 5 or 6 positions of the phenyl moiety. When xe2x80x9cAr2xe2x80x9d isinaphthyl, it is understood that the radical can be attached at the either the 1-position or the 2-position, it is further understood that when the radical is attached at the 1-position the substituent or substituents can be attached in any of the 2, 3, 4, 5, 6, 7, or 8 positions and that when the radical is attached at the 2-position the substituent or substituents can be attached in any of the 1, 3, 4, 5, 6, 7, or 8 positions.
n) the term xe2x80x9chalogenxe2x80x9d refers to fluorine, chlorine, bromine or iodine.
o) the term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d thereof refers to either an acid addition salt or a basic addition salt.
The expression xe2x80x9cpharmaceutically acceptable acid addition saltsxe2x80x9d is intended to apply to any non-toxic organic or inorganic acid addition salt of the base compounds represented by formula (1) or any of its intermediates. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulphuric, and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate, and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include the mono-, di-, and tricarboxylic acids. Illustrative of such acids are for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicyclic, 2-phenoxybenzoic, p-toluenesulfonic acid, and sulfonic acids such as methane sulfonic acid and 2-hydroxyethane sulfonic acid. Such salts can exist in either a hydrated or substantially anhydrous form. In general, the acid addition salts of these compounds are soluble in water and various hydrophilic organic solvents, and which in comparison to their free base forms, generally demonstrate higher melting points.
The expression xe2x80x9cpharmaceutically acceptable basic addition saltsxe2x80x9d is intended to apply to any non-toxic organic or inorganic basic addition salts of the compounds represented by formula (1) or any of its intermediates. Illustrative bases which form suitable salts include alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calcium, magnesium, or barium hydroxides; ammonia, and aliphatic, alicyclic, or aromatic organic amines such as methylamine, dimethylamine, trimethylamine, and picoline.
The term xe2x80x9cstereoisomersxe2x80x9d is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes mirror image isomers (enantiomers), geometric (cis/trans) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers). Any reference in this application to one of the compounds of formula (1) is meant to encompass either specific stereoisomers or a mixture of stereoisomers. The specific stereoisomers can be prepared by stereospecific synthesis or can be separated and recovered by techniques known in the art, such as chromatography, chromatography on chiral stationary phases, fractional recrystallization of addition salts formed by reagents used for that purpose, as described in Stereochemistry of Organic Compounds, E. L. Eliel and S. H. Wilen, Wiley (1994) and Enantiomers, Racemates, and Resolutions, J. Jacques, A. Collet, and S. H. Wilen, Wiley (1981).
As with any group of structurally related compounds which possess a particular utility, certain groups and configurations of substituents are preferred for the compounds of formula (1). Preferred embodiments are given below:
1) A preferred embodiment of the novel compounds is that of formula (1) are compounds in which R3 is C1-C6 alkyl.
2) A preferred embodiment of the novel compounds is that of formula (1) are compounds in which R3 is a Qxe2x80x94Zxe2x80x94(CH2)mxe2x80x94 group.
3) A preferred embodiment of the novel compounds is that of formula (1) are compounds in which R2 is a xe2x80x94(CH2)pxe2x80x94Ar1 group wherein Ar1 is phenyl optionally substituted with F, Cl, C1-C4 alkyl, or xe2x80x94OR7.
4) A preferred embodiment of the novel compounds is that of formula (1) are compounds in which R1 is a a xe2x80x94(CH2)pxe2x80x94A group, wherein A is C6-C10 aryl.
5) A preferred embodiment of the novel compounds is that of formula (1) are compounds in which R3 is a Wxe2x80x94(CH2)mxe2x80x94 group.
6) A preferred embodiment of the novel compounds is that of formula (1) are compounds in which R4 is hydrogen.
7) A preferred embodiment of the novel compounds is that of formula (1) are compounds in which R4 is xe2x80x94C(O)R7.
8) A preferred embodiment of the novel compounds is that of formula (1) are compounds in which R4 is a xe2x80x94Sxe2x80x94G group.
9) A more preferred embodiment of the novel compounds is that of formula (1) are compounds in which R1 is a a xe2x80x94(CH2)pxe2x80x94A group, wherein A is phenyl or optionally substituted phenyl.
10) A more preferred embodiment of the novel compounds is that of formula (1) are compounds in which R3 is C1-C6 alkyl, preferably methyl, ethyl, propyl, isopropyl, butyl or isobutyl; R2 is xe2x80x94(CH2)pxe2x80x94Ar1 group wherein p is 0 and Ar1 is phenyl optionally substituted with F, Cl, C1-C4 alkyl, or xe2x80x94OR7; and R4 is hydrogen, xe2x80x94C(O)R7, or a xe2x80x94Sxe2x80x94G group.
11) A more preferred embodiment of the novel compounds is that of formula (1) are compounds in which R3 is a Wxe2x80x94(CH2)mxe2x80x94 group; R2 is xe2x80x94(CH2)pxe2x80x94Ar1 group wherein p is 0 and Ar1 is phenyl optionally substituted with F, Cl, C1-C4 alkyl, or xe2x80x94OR7; and R4 is hydrogen, xe2x80x94C(O)R7, or a xe2x80x94Sxe2x80x94G group.
Examples of compounds encompassed by the present invention include the following. It is understood that the examples encompass all of the isomers of the compound and mixtures thereof. This list is meant to be representative only and is not intended to limit the scope of the invention in any way:
N-[Hexahydro-1-[1-(phenylethyl)-1-carboxymethyl]-2-oxo-5-phenyl-1H-azepin-3-yl]-1,3-dihydro-xcex1-mercapto-1,3-dioxo-2H-isoindole-2-hexanamide;
N-[Hexahydro-1-[1-(phenylmethyl)-1-carboxymethyl]-2-oxo-5-phenyl-1H-azepin-3-yl]-xcex1-mercapto-3-phenylpropionamide;
N-[Hexahydro-1-[1-(phenylmethyl)-1-carboxymethyl]-2-oxo-5-phenyl-1H-azepin-3-yl]-xcex1-mercapto-4-methylbutamide;
N-[Hexahydro-1-[1-(phenylmethyl)-1-carboxymethyl]-2-oxo-5-phenyl-1H-azepin-3-yl]-1,3-dihydro-xcex1-mercapto-1,3-dioxo-2H-isoindole-2-pentamide;
N-[Hexahydro-1-[1-(phenylmethyl)-1-carboxymethyl]-2-oxo-5-phenyl-1H-azepin-3-yl]-1,3-dihydro-xcex1-mercapto-1,3-dioxo-2H-isoindole-2-heptaamide;
N-[Hexahydro-1-[1-(phenylmethyl)-1-carboxymethyl]-2-oxo-5-phenyl-1H-azepin-3-yl]-1,3-dihydro-xcex1-acetylthio-1,3-dioxo-2H-isoindole-2-hexanamide;
N-[Hexahydro-1-[1-(phenylmethyl)-1-carboxymethyl]-2-oxo-5-phenyl-1H-azepin-3-yl]-1,3-dihydro-xcex1-benzoylthio-1,3-dioxo-2H-isoindole-2-hexanamide;
N-[Hexahydro-1-[1-(phenylmethyl)-1-carboxymethyl]-2-oxo-5-phenyl-1H-azepin-3-yl]-1,3-dihydro-xcex1-ethyldithio-1,3-dioxo-2H-isoindole-2-hexanamide; and
N-[Hexahydro-1-[1-(phenylmethyl)-1-carboxymethyl]-2-oxo-5-phenyl-1H-azepin-3-yl]-1,3-dihydro-xcex1-(2-hydroxyethyl)dithio-1,3-dioxo-2H-isoindole-2-hexanamide.
The compounds of formula (1) can be prepared by utilizing techniques and procedures well known and appreciated by one of ordinary skill in the art. A general synthetic scheme for preparing these compounds is set forth in Scheme A wherein all substituents are as previously defined unless otherwise indicated. 
Scheme A provides a general synthetic procedure for preparing compounds of formula (1). The substituents R1, R2, R3, and R4 are defined as above, while the substituent R4xe2x80x2 is defined as xe2x80x94C(O)R7.
In Scheme A, step a, the appropriate R2-substituted cyclohexanone of structure (2) is enolized with a non-nucleophilic base and quenched with a suitable electrophile, such as chlorotrimethylsilane, to form the corresponding R2-substituted enol ether, followed by treatment with ozone, dimethylsulfide, trimethylortho-formate and a suitable base to provide the appropriate R2-substituted acid of structure (3). R2-substituted cyclohexanones of structure (2) are commercially available, known in the art, or can be prepared as described herein.
For example, lithium diisopropylamide (LDA) is generated by the addition of n-butyllithium to di-isopropylamine in the presence of a suitable organic solvent such as tetrahydrofuran (THF). A solution of R2-substituted cyclohexanone of structure (2) in a suitable organic solvent, such as tetrahydrofuran, is then added at xe2x88x9278xc2x0 C. After a period of time ranging from about 1 to 3 hours, the reaction is quenched with chloromethylsilane and the mixture is stirred followed by extraction and concentration of the organic layer to yield the silyl enol ether intermediate.
The silyl enol ether intermediate is then dissolved in a suitable organic solvent or solvent mixture, such as a methylene chloride/methanol mixture, cooled to xe2x88x9278xc2x0 C. and treated with ozone. Dimethyl sulfide is added and the reaction mixture is allowed to warm gradually to ambient temperature over a period of time ranging from 10 to 20 hours. The solution is then concentrated and treated with an orthoformate reagent such as trimethylorthoformate and an acid source such as acetyl chloride and heated to reflux. After a period of time ranging from 4 to 6 hours, the mixture is cooled to ambient temperature and treated with a suitable base, such as potassium hydroxide. The appropriate R2-substituted acid of structure (3) can be isolated by methods well known and appreciated in the art, such as extraction and evaporation.
In Scheme A, step b, the appropriate R2-substituted acid of structure (3) is reacted with lithiated (S)-4-benzyl-2-oxazolidinone to provide the appropriate acyloxazolidinone of structure (4). As depicted in Scheme A, the use of (S)-4-benzyl-2-oxazolidinone in Scheme A gives rise to a 3-aminoazepan having the (S)-configuration at the 3-position. As is appreciated by those skilled in the art, the use of (R)-4-benzyl-2-oxazolidinone would give a 3-aminoazepan having the opposite configuration if desired in the final product of formula (1).
For example, the appropriate R2-substituted acid of structure (3) in a suitable organic solvent, such as tetrahydrofuran, is treated with a suitable tertiary organic amine such as triethylamine or N-methylmorpholine and cooled to xe2x88x9278xc2x0 C. A suitable acid halide such as trimethylacetyl chloride is added and the mixture is transferred to an ice bath for 0.5 to 1.0 hours, then recooled to xe2x88x9278xc2x0 C. The resulting slurry is treated with lithiated (S)-4-benzyl-2-oxazolidinone, prepared by adding n-butyllithium to (S)-4-benzyl-2-oxazolidinone in tetrahydrofuran, and allowed to warm gradually to ambient temperature over a period of time ranging from about 10 to 20 hours. The appropriate acyloxazolidinone of structure (4) can be isolated by methods well known and appreciated in the art, such as extraction and evaporation. The product can be purified by methods well known and appreciated in the art, such as flash chromatography.
In Scheme A, step c, the appropriate acyloxazolidinone of structure (4) undergoes an azide introduction reaction with a suitable azide transfer agent to provide the appropriate xcex1-azidoacyloxazolidinone of structure (5).
For example, a solution of a suitable amide such as potassium bis(trimethylsilyl)amide in a suitable organic solvent, such as tetrahydrofuran, is cooled to xe2x88x9278xc2x0 C. and treated with a solution of the appropriate acyloxazolidinone of structure (4) in tetrahydrofuran, precooled to xe2x88x9278xc2x0 C. A solution of a suitable azide transfer agent, such as triisopropylbenzenesulfonyl azide, in a suitable organic solvent, such as tetrahydrofuran, precooled to xe2x88x9278xc2x0 C. is then added. The solution is stirred, quenched with acetic acid and transferred to an oil bath having a temperature of from about 25-40xc2x0 C. After a period of time ranging from about 1 to 2 hours, the suspension is cooled to ambient temperature and water is added to obtain a solution. The appropriate xcex1-azidoacyloxazolidinone of structure (5) can be isolated by methods well known and appreciated in the art, such as extraction and evaporation. The product can be purified by methods well known in the art, such as flash chromatography.
In Scheme A, step d, the appropriate xcex1-azidoacyloxazolidinone of structure (5) is converted to the corresponding xcex1-azidoacid and then reacted with 2-trimethylsilylethanol to give the corresponding xcex1-azidoester of structure (6). It is understood that protecting groups other than 2-trimthylsilyl may be introduced. The only requirements for this protecting group are that it is stable to the conditons used in Scheme A, steps e and f and that it can be selectively removed in the presence of the protecting group, Pg, introduced in the carboxy protected amino acid (7a). The use and selective removal of carboxy protecting groups is well known and appreciated in the art and described in Protective Groups in Organic Synthesis, Theodora W. Greene (Wiley-Interscience, 2nd Edition, 1991).
For example, the appropriate xcex1-azidoacyloxazolidinone of structure (5) in a suitable solvent such as tetrahydrofuran or tetrahydrofuran/water mixtures, is cooled and treated with hydrogen peroxide and a suitable base, such as lithium hydroxide. The mixture is stirred for about 1 to 2 hours and allowed to warm to ambient temperature and treated with sodium sulfite. The corresponding xcex1-azidoacid is isolated by methods well known and appreciated in the art, such as extraction and evaporation.
The corresponding xcex1-azidoacid in a suitable organic solvent, such as tetrahydrofuran, is then treated sequentially at ambient temperature with 2-trimethylsilylethanol, an organic amine, such as pyridine, and a condensing agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC). The mixture is then stirred for about 1 to 3 days and then concentrated. The corresponding xcex1-azidoester of structure (6) can be isolated by methods well known and appreciated in the art, such as extraction and evaporation. The product can be purified by methods well known and appreciated in the art, such as flash chromatography.
In Scheme A, step e, the xcex1-azidoester of structure (6) is contacted with a suitable organic acid to provide the corresponding aldehyde-ester of structure (7).
For example, a solution of xcex1-azidoester of structure (6) in the presence of a suitable organic acid, such as acetic acid, and a suitable organic solvent, such as a tetrahydrofuran/water mixture, is heated at a temperature ranging from about 55xc2x0 C. to about 70xc2x0 C. for about 3 to 5 hours. The solution is then cooled and the corresponding aldehyde-ester of structure (7) is isolated by methods well known and appreciated in the art, such as extraction and evaporation. The product can be purified by methods well known and appreciated in the art, such as flash chromatography.
In Scheme A, step f, the aldehyde-ester of structure (7) undergoes a reductive, amination with an carboxy protected amino acid of structure (7a), or a salt thereof, to provide the corresponding amino-ester of structure (8). Suitable carboxy protected amino acids, including their specific stereoisomers, are commercially available, are prepared from amino acid starting materials which are commercially available, or can be prepared by stereospecific synthesis as is well known in the art or analogously known in the art, such as D. A. Evans, et al. J. Am. Chem. Soc., 112, 4011-4030 (1990); S. Ikegami et al. Tetrahedron, 44, 5333-5342 (1988); W. Oppolzer et al. Tet. Lets. 30, 6009-6010 (1989); Synthesis of Optically Activexcex1-Amino-Acids, R. M. Williams (Pergamon Press, Oxford 1989); M. J. O""Donnell ed.: xcex1-Amino-Acid Synthesis, Tetrahedron Symposia in print, No. 33, Tetrahedron 44, No. 17 (1988); U. Schxc3x6llkopf, Pure Appl. Chem. 55, 1799 (1983); U. Hengartner et al. J. Org. Chem., 44, 3748-3752 (1979); M. J. O""Donnell et al. Tet. Lets., 2641-2644 (1978); M. J. O""Donnell et al. Tet. Lets. 23, 4255-4258 (1982); M. J. O""Donnell et al. J. Am. Chem. Soc., 110, 8520-8525 (1988).
For example, a solution of the aldehyde ester of structure (7) and a carboxy protected amino acid of structure (7a) in a hydroxylic solvent, such as methanol or ethanol, is treated with powdered activated 3 xc3x85 sieves. After about 30 minutes to 1 hour, the solution is reacted with a suitable reducing agent such as sodium cyanoborohydride, lithium cyanoborohydride, and the like. The amino-ester of structure (8) is isolated by methods well known and appreciated in the art, such as extraction and evaporation. The product can be purified by methods well known and appreciated in the art, such as flash chromatography.
In Scheme A, step g, the amino-ester of structure (8) is cyclized, after selected carboxy protecting group removal, to give a mixture of the cis xcex1-azidolactam of structure (9) and the trans xcex1-azidolactam of structure (10).
For example, where the 2-trimethylsilyl protecting group is used, a solution of the amino-ester of structure (8) in a suitable organic solvent, such as tetrahydrofuran, is treated at ambient temperature with a fluoride ion source, such as tetra-n-butylammonium fluoride, and stirred. After about 2 to 4 hours, the solution is concentrated. The residue is then dissolved in a suitable organic solvent, such as ethyl acetate, washed with a suitable acid, such as 10% aqueous hydrochloric acid, and brine. The organic layer is then dried and concentrated to yield the corresponding crude amino acid.
The crude amino acid is then dissolved in a suitable organic solvent, such as tetrahydrofuran, cooled in an ice bath and treated sequentially with a suitable tertiary amine, such as N-methylmorpholine, and isobutyl chloroformate. The suspension is stirred for about 2 to 3 hours and filtered. The salts are washed with dry tetrahydrofuran and the filtrate is concentrated. The residue may be purified by methods well known and appreciated in the art, such as radial chromatography, to afford separately, the cis xcex1-azidolactam of structure (9) and the trans xcex1-azidolactam of structure (10).
In Scheme A, steps h1 and h2, the cis xcex1-azidolactam of structure (9) and the trans xcex1-azidolactam of structure (10), respectively, are converted to the corresponding cis xcex1-aminolactam of structure (11) and the trans (xcex1-aminolactam of structure (12), respectively.
For example, a solution of cis xcex1-azidolactam of structure (9) or trans xcex1-azidolactam of structure (10) in a protic solvent, such as methanol or ethanol, is degassed and treated with an alkyl dithiol, such as 1,3-propanedithiol and a tertiary amine, such as triethylamine. The solution is stirred from 60 to 72 hours and then concentrated. The residue may be purified by methods well known and appreciated in the art, such as flash chromatography, to afford the corresponding cis xcex1-aminolactam of structure (11) or the trans xcex1-aminolactam of structure (12), respectively.
In Scheme A, steps i1 and i2, the cis xcex1-aminolactam of structure (11) and the trans xcex1-aminolactam of structure (12), respectively, are coupled with the bromoacid of structure (12a) to provide the bromoamides of structures (13) and (14), respectively. Suitable bromoacids are commercially available or can be prepared utilizing materials, techniques, and procedures well known and appreciated by one of ordinary skill in the art or described herein. See PCT Application WO 96/11209, published 18 Apr. 1996. Examples of commercially available bromoacids include 2-bromopropionic acid, 2-bromobutyric acid, 2-bromovaleric acid, 2-bromohexanoic acid, 6-(benzoylamino)-2-bromohexanoic acid, 2-bromoheptanoic acid, 2-bromooctanoic acid, 2-bromo-3-methylbutyric acid, 2-bromoisocaproic acid, 2-bromo-3-(5-imidazoyl)propionic acid, (R)-(+)-2-bromopropionic acid, (S)-(xe2x88x92)-2-bromopropionic acid.
For example, a mixture of cis xcex1-aminolactam of structure (11) or trans xcex1-aminolactam of structure (12), a bromoacid of structure (12a), a carbodiimide, such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), and 1-hydroxybenzotriazole (HOBt) in a suitable organic solvent such as methylene chloride was stirred at ambient temperature for 15 to 25 hours. The cis bromoamide of structure (13) or the trans bromoamide of structure (14) may be isolated by methods well known and appreciated in the art, such as extraction and evaporation. The product can be purified by methods well known and appreciated in the art, such as flash chromatography.
In Scheme A, steps j1 and j2, the cis bromoamide of structure (13) and the trans bromoamide of structure (14), respectively, are converted to the cis xcex1-thioamide of structure (15) and the trans xcex1-thioamide of structure (16), respectively. This displacement reaction can be carried out using an appropriate thio introducing reagent to give compound of formula (15) and (16) having a protected thio substituent. Such protected thio substituents give rise upon deprotection and subsequent elaboration, if desired, the xe2x80x94SR4 as desired in the final compound of formula (1). An appropriate thio introducing reagent is also one which introduces a group xe2x80x94SF4 as desired in the final compound of formula (1), such as thioacetyl or thiobenzoyl or the group xe2x80x94SC(O)xe2x80x94(CH2)qxe2x80x94K.
For example, a solution of p-methoxybenzylmercaptan in a suitable organic solvent such as dimethylformamide is degassed and treated with a suitable base such as sodium hydride. After about 1 to 2 hours, a solution of bromoamide of structure (13) or structure (14) in a suitable organic solvent, such as dimethylformamide is added to the mercaptide formed immediately above, as well as a suitable phase transfer catalyst, such as tetra-n-butylammonium iodide. The reaction mixture is stirred for 15 to 25 hours and saturated aqueous ammonium chloride solution and water are added. The cis xcex1-thioamide of structure (15) or the trans xcex1-thioamide of structure (16), respectively, may be isolated by methods well known and appreciated in the art, such as extraction and evaporation. The product can be purified by methods well known and appreciated in the art, such as flash chromatography.
In Scheme A, steps k1 and k2, cis xcex1-thioamide of structure (15) and the trans xcex1-thioamide of structure (16), respectively, are cleaved to provide the compounds of structures (17) and (18), respectively.
For example, a mixture of cis xcex1-thioamide of structure (15) or the trans xcex1-thioamide of structure (16), mercuric acetate and anisole in a suitable organic solvent, such as methylene chloride is cooled in an ice bath, degassed, and treated with a suitable acid, such as trifluoroacetic acid. After a time period of about 3-6 hours, hydrogen sulfide gas is bubbled in the reaction mixture for about 10 to 20 minutes. The compounds of structures (17) and (18) may be isolated by methods well known and appreciated in the art, such as extraction and evaporation. The product can be purified by methods well known and appreciated in the art, such as flash chromatography.
In Scheme A, optional steps l1 and l2, the thiol functionality of compounds (17) and (18) are acylated, if desired, with an R4xe2x80x2-acylating agent wherein R4xe2x80x2 is defined as above, to provide the compounds (17a) and (18a).
For example, the appropriate compound of structures (17) or (18) can be contacted with a molar equivalent of an appropriate R4xe2x80x2-acylating agent such as acetic anhydride and a catalytic amount of an acid such as sulfuric acid. The reactants are typically stirred together for a period of time ranging from 10 minutes to 10 hours. The compounds of structures (17a) and (18a) may be isolated by methods well known and appreciated in the art, such as extraction and evaporation. The products can be purified by methods well known and appreciated in the art, such as flash chromatography.
In Scheme A, step m, a compound of formula (17), (18), (17a), or (18a) is deprotected to give a compound of formula (1). Such deprotection reactions are well known appreciated in the art and may include selective deprotections in which the carboxy protecting group (Pg) and protecting groups on R1, R2, R3, and R4 are removed if desired.
R2-substituted cyclohexanones of structure (2) can be prepared by utilizing techniques and procedures well known and appreciated by one of ordinary skill in the art. A general synthetic scheme for preparing these compounds is set forth in Scheme B wherein all substituents are as previously defined unless otherwise indicated. 
Scheme B provides a general synthetic procedure for preparing compounds of formula (2) wherein the substituents are defined as above, unless otherwise indicated.
In Scheme B, step a, the ketone of structure (2d) is reacted with an organolithium compound of the formula R2Li or a Grignard reagent of the formula R2Mg-Hal, where xe2x80x9cHalxe2x80x9d is halogen, according to techniques well known in the art to provide the tertiary alcohol of structure (2c).
For example, an appropriate Grignard reagent of structure R2MgBr in a suitable organic solvent, such as ethyl ether is added to a solution of the ketone of structure (2d) in a suitable organic solvent, such as anhydrous ethyl ether. The reaction mixture is stirred and then cooled to about 0xc2x0 C. Saturated ammonium chloride solution is then added. The ethereal layer is separated, washed with water and dried (MgSO4). The solvent is evaporated in vacuo and purified by silica gel chromatography to give the tertiary alcohol of structure (2c).
An appropriate Grignard reagent of structure R2Mg-Hal can be prepared by techniques well known in the art. For example, magnesium turnings and anhydrous ethyl ether are mixed under an inert atmosphere. A solution of a compound of the formula R2-Hal, where xe2x80x9cHalxe2x80x9d is halogen, in ethyl ether is then added to the magnesium mixture. The mixture is then stirred until the magnesium metal dissolves to give the Grignard reagent of structure R2Mg-Hal.
In Scheme B, step b, the tertiary alcohol of structure (2c) is dehydrated according to techniques well known in the art to give the intermediate of structure (2b).
For example, the tertiary alcohol of structure (2c) may be dehydrated according to the procedure disclosed by Yadav, J. S. and Mysorekar, S. V., Synth. Comm. 19, 1057-1060 (1989). For example, to a stirred solution of the tertiary alcohol of structure (2c) in methylene chloride is added triethylamine and DMAP. The mixture is then cooled to about 0xc2x0 C. and methanesulfonyl chloride is added dropwise to the mixture. The resulting reaction mixture is stirred for about 1 hour at room temperature. Crushed ice is added and the mixture stirred for about 1 hour. Afterwards, the reaction mixture is extracted with methylene chloride. The organic extracts are combined, washed with water and dried (Na2SO4). The solvent is then evaporated and the products are purified by methods well known and appreciated in the art, such as silica gel chromatography to provide the intermediate of structure (2b).
In Scheme B, step c, the intermediate of structure (2b) is reduced to provide the ketal of structure (2a).
For example, a solution of the intermediate of structure (2b) in a suitable organic solvent, such as methanol, may be treated with 10% palladium/carbon catalyst (Pdxe2x80x94C) and stirred under a hydrogen atmosphere for a period of from 10-20 hours. Additional catalyst may then be added, the mixture may be stirred for an additional 5-10 hours, degassed and filtered. The filtrate is then concentrated to yield the ketal of structure (2a).
In Scheme B, step d, the ketal of structure (2a) is hydrolyzed according to procedures well known in the art to provide the R2-substituted cyclohexanone of structure (2). For example, the blocked ketone functionality of the compound of structure (2a) may be hydrolyzed according to the procedure disclosed by Honan, M. C., Tetrahedron Lett. 26, 6393-6396 (1985) or Greico, P. A. et al., J. Amer. Chem. Soc. 99, 5773-5780 (1977). For example, the ketal of structure (2a) is dissolved in a solution of a tetrahydrofuran/5% hydrochloric acid mixture (2:1) and allowed to react for a period of time ranging from about 15 to 25 hours at room temperature. The solvent is then removed under reduced pressure to afford the R2-substituted cyclohexanone of structure (2).
The bromoacids of structure (12a) wherein R3 is a Wxe2x80x94(CH2)mxe2x80x94 group are synthesized according to Scheme C. The bromoacid of structure (35) corresponds to the bromoacid of structure (12a) when R3 is a Wxe2x80x94(CH2)mxe2x80x94 group. In Scheme 3, W is represented by PhtN, wherein W is phthalimido. 
In Scheme C, step a, the amino carboxylic acid of structure (33) in a suitable polar solvent, such as water or a water/ethereal solvent mixture, is treated with sodium carbonate and N-carbethoxy phthalimide (NCEP). The reaction mixture is typically stirred at ambient temperature for 1-5 hours and extracted by extractive methods well known in the art. The aqueous layer is then cooled and acidified to about pH 1 using an acid, such as concentrated hydrochloric acid. The precipitate is then collected by filtration, washed with water and then dried to give the phthalimido carboxylic acid of structure (34).
In Scheme C, step b, the phthalimido carboxylic acid of structure (34) is brominated to give the 2-bromo-phthalimido carboxylic acid of structure (35). For example, a mixture of the phthalimido carboxylic acid of structure (34) and dry red phosphorous is treated dropwise with bromine at temperature ranging from about xe2x88x9220xc2x0 to about 10xc2x0 C. The reaction mixture is then warmed to room temperature and then heated to about 80xc2x0 C. for about 2-5 hours. The reaction mixture is then cooled to room temperature, poured into water containing sodium bisulfite, and neutralized using solid NaHCO3. The aqueous layer is washed with an ethereal solvent, such as diethyl ether, and acidified with a suitable acid, such as concentrated hydrochloric acid. The precipitate is collected by filtration and dried to yield the bromoacid of structure (35).
Alternatively, the bromoacid of structure (35) can be prepared following the procedure described in Scheme C, steps a1, a2 and b1, as described analogously by Baldwin, J. E. et al., Tetrahedron 44, 2633-2636 (1988) and Bezas, B. and Zervas, L., J. Am. Chem. Soc. 83, 719-722 (1961).
For example, in Scheme C, step a1, selective N-xcex1-protection of a suitable xcex1-amino acid, such as L-lysine, is accomplished by masking the xcex5-amino group by formation of a benzylidene imine. The benzylidene imine is formed by dissolving L-lysine monohydrochloride in lithium hydroxide and cooling the solution to a temperature ranging from about 0xc2x0 to 10xc2x0 C. Freshly distilled benzaldehyde is then added and the solution is shaken. N-xcex5-benzylidene-L-lysine is recovered by filtration and evaporation.
The xcex1-amino group of the N-xcex5-benzylidene-L-lysine then undergoes urethane protection, followed by hydrolytic cleavage of the imine in situ to give N-xcex1-benzyloxycarbonyl-L-lysine. For example, N-xcex5-benzylidene-L-lysine is added to a mixture of sodium hydroxide and ethanol, cooled to a temperature of from about xe2x88x925xc2x0 to about xe2x88x9225xc2x0 C. Then, precooled solutions of benzyloxycarbonyl chloride in an alkaline solvent, such as sodium hydroxide and ethanol, are added to the reaction mixture. The temperature is maintained at a temperature ranging from about xe2x88x9210xc2x0 to about xe2x88x9225xc2x0 C. during the course of addition, and then allowed to rise slightly (approx. xe2x88x925xc2x0 C.) with stirring. The reaction mixture is then acidified using a suitable acid, such as precooled hydrochloric acid, and N-xcex1-benzyloxycarbonyl-L-lysine, which corresponds to structure (34a) where m is 4, is recovered by filtration and recrystallization.
In Scheme C, step a2, N-xcex1-benzyloxycarbonyl-L-lysine or other compounds of structure (34a) are reacted with N-carboethoxyphthalimide in aqueous sodium carbonate solution to yield optically pure phthaloyl derivatives of the compounds of structure (34a).
The phthaloyl derivatives of the compounds of structure (34a) are then reduced concurrently with carbobenzloxy hydrogenolysis to give the N-xcex5-phthaloyl amino acids of structure (34b). For example, the individual phthaloyl derivative of structure (34a) is contacted with a catalytic amount of a hydrogenation catalyst, such as 10% palladium/carbon. The reactants are typically contacted in a suitable solvent mixture such as tetrahydrofuran/water. The reactants are typically shaken under a hydrogen atmosphere of 35-45 psi at room temperature for a period of time ranging from 5-24 hours. The individual N-xcex5-phthaloyl amino acid of structure (34b) is recovered from the reaction zone by evaporation of the solvent.
In Scheme C, step b1, the individual N-xcex5-phthaloyl amino acid of structure (34b) is deaminobrominated to yield the bromoacid of structure (35). This reaction can be performed utilizing a reaction of the type described in Compagnone, R. S. and Rapoport, H., J. Org. Chem., 51, 1713-1719 (1986); U.S. Pat. No. 5,322,942, issued Jun. 21, 1994; Overberger, C. G. and Cho, I., J. Org. Chem., 33, 3321-3322 (1968); or Pfister, K. et al., J. Am. Chem. Soc., 71, 1096-1100 (1949).
For example, a mixture of N-xcex5-phthaloyl amino acid of structure (34b) and a suitable bromide, such as hydrogen bromide or potassium bromide, in acidic solution, such as sulfuric acid, is treated with sodium nitrite. If avoidance of racemization caused by excess bromide ion is desired, the reaction temperature can be kept between xe2x88x925xc2x0 C. and 0xc2x0 C. during addition and stirring. After the reaction mixture is stirred for a period of time ranging from 1.5 to 5 hours, the bromoacid of structure (35) may be recovered by extraction and evaporation.
The bromoacids of structure (12a) wherein R3 is C1-C6 alkyl or a Qxe2x80x2xe2x80x94Zxe2x80x2xe2x80x94(CH2)mxe2x80x94 group, wherein m is as defined above and Qxe2x80x2 is hydrogen or a Yxe2x80x2xe2x80x94(CH2)nxe2x80x94 group, wherein Yxe2x80x2 is xe2x80x94C(O)OR6; Zxe2x80x2 is a bond, oxy or amino, are synthesized according to Scheme D. The bromoacid of structure (37) corresponds to the bromoacid of structure (12a) when R3 is C1-C6 alkyl, or a Qxe2x80x2xe2x80x94Zxe2x80x2xe2x80x94(CH2)mxe2x80x94 group. 
Scheme D provides a general synthetic procedure for preparing the bromoacids of structure (12a) when R3 is C1-C6 alkyl or a Qxe2x80x2xe2x80x94Zxe2x80x2xe2x80x94(CH2)mxe2x80x94 group, signified as structure (37). The substituent R3xe2x80x2 is defined as C1-C6 alkyl, or a Qxe2x80x2xe2x80x94Zxe2x80x2xe2x80x94(CH2)mxe2x80x94 group.
In Scheme D, an appropriate amino acid of structure (36) is deaminobrominated to yield the R3xe2x80x2-substituted bromoacid of structure (37) as described previously in Scheme C, step b1.
The amino acids of structure (36), and N-protected forms thereof, are commercially available or may be readily prepared by techniques and procedures well known and appreciated by one of ordinary skill in the art. For example, L-alanine, D-alanine, L-valine, D-valine, D-norvaline, L-leucine, D-leucine, D-isoleucine, D-tert-leucine, glycine, L-glutamic acid, D-glutamic acid, L-glutamine, D-glutamine, L-lysine, D-lysine, L-ornithine, D-ornithine, (D)-(xe2x88x92)-2-aminobutyric acid, D-threonine, D-homoserine, D-allothreonine, D-serine, D-2-aminoadipic acid, D-aspartic acid, D-glutamic acid, D-lysine hydrate, 2,3-diaminopropionic acid monohydrobromide, D-omithine hydrochloride, D,L-2,4-diaminobutyric acid dihydrochloride, L-meta-tyrosine, D-4-hydroxyphenylglycine, D-tyrosine, D-phenylalanine, D,L-2-fluorophenylalanine, beta-methyl-D,L-phenylalanine hydrochloride, D,L-3-fluorophenylalanine, 4-bromo-D,L-phenylalanine, D-2-phenylglycine, D,L-4-fluorophenylalanine, 4-iodo-D-phenylalanine, D-homophenylalanine, D,L-2-fluorophenylglycine, D,L-4-chlorophenylalanine, and the like, are all commercially available from Sigma Chemical Co., St. Louis, Mo. or Aldrich Chemical Co., Inc.
The cis xcex1-thioamide of structure (15), the trans xcex1-thioamide of structure (16), and the xcex1-thioamide of structure (31) where R3 is a Qxe2x80x22xe2x80x94Zxe2x80x22xe2x80x94(CH2)mxe2x80x94 group wherein Qxe2x80x22 is a Yxe2x80x22xe2x80x94(CH2)nxe2x80x94 group, where Yxe2x80x22 is xe2x80x94N(R6)2, can be synthesized according to techniques well known and appreciated by one of ordinary skill in the art. A general synthetic scheme for preparing these compounds is set forth in Scheme F wherein all substituents, unless otherwise indicated, are previously defined. The xcex1-thioamide of structure (38) generically represents the cis xcex1-thioamide of structure (15), the trans xcex1-thioamide of structure (16), and the xcex1-thioamide of structure (31) when R1 is a Qxe2x80x22xe2x80x94Zxe2x80x22xe2x80x94(CH2)mxe2x80x94 group wherein Qxe2x80x22 is a Yxe2x80x22xe2x80x94(CH2)nxe2x80x94 group, where Yxe2x80x22 is xe2x80x94N(R6)2.
Schemes F-Q provide for compounds which give rise to compounds of formula (1) upon deprotection or selective deprotection of the carboxy protecting group, Pg. Such deprotections or selective deprotection reactions are well known appreciated in the art.
Scheme F provides compounds of structure (39) and (40) which give rise to compounds of formula (1) in which Z is an amine or a substituted amine. Scheme F also provides compounds of structure (41) which give rise to commands of formula (1) in which Z is a bond and Q is xe2x80x94N(R6)2. 
Scheme F provides a general synthetic procedure for preparing compounds of structures (15), (16) and (41) wherein R3 is a Qxe2x80x22xe2x80x94Zxe2x80x22xe2x80x94(CH2)mxe2x80x94 group wherein Qxe2x80x22 is a Yxe2x80x22xe2x80x94(CH2)nxe2x80x94 group, where Yxe2x80x22 is xe2x80x94N(R6)2, and Zxe2x80x22 is a bond. All of the substituents are as defined above except R6xe2x80x2 which is defined as C1-C6 alkyl.
In Scheme F, step a, the phthalimido group of the appropriate individual xcex1-thioamide compounds of structure (38) is contacted with a molar excess of hydrazine monohydrate. The reactants are typically contacted in a protic organic solvent, such as methanol. The reactants are typically stirred together at room temperature for a period of time ranging from 5-24 hours. The corresponding free amine compounds of structure (39) are recovered from the reaction zone by evaporation of the solvent, redissolving in chloroform, filtration to remove phthal-hydrazide and removal of the chloroform in vacuo.
In Scheme F, optional step b, the individual free amines of structure (39) are converted to the R6xe2x80x2-substituted amines of structure (40) by reductive alkylation.
For example, a mixture of the free amine of structure (39) in a protic organic solvent, such as methanol, is contacted with R6xe2x80x2CHO, sodium cyanoborohydride and 1 drop of 1% bromocresol green in methanol. The pH of the reaction is maintained with 1N hydrochloric acid in methanol. The R6xe2x80x2-substituted amines of structure (40) are recovered from the reaction zone by extraction and evaporation of the solvent.
In Scheme F, optional step c, the R6xe2x80x2-substituted amines of structure (40) is converted to the di-R6xe2x80x2-substituted amines of structure (41) as described above in Scheme D, optional step b.
The cis xcex1-thioamide of structure (15), the trans xcex1-thioamide of structure (16), and the xcex1-thioamide of structure (41) where R3 is a Qxe2x80x23xe2x80x94Zxe2x80x23xe2x80x94(CH2)mxe2x80x94 group, wherein Qxe2x80x23 is a Yxe2x80x23xe2x80x94(CH2)nxe2x80x94 group, Zxe2x80x23 is CONR6, and Yxe2x80x23 is H, C6-C10 aryl, C3-C9 heteroaryl morpholino, piperidino, pyrrolidino or isoindolyl can be synthesized according to techniques well known and appreciated by one of ordinary skill in the art. A general synthetic scheme for preparing these compounds, signified as the compounds of structure (43), is set forth in Scheme G wherein all substituents, unless otherwise indicated, are previously defined. 
Scheme G provides a general synthetic procedure for preparing compounds of structures (15), (16) and (41) wherein R3 is a Qxe2x80x23xe2x80x94Z3xe2x80x94(CH2)mxe2x80x94 group wherein Qxe2x80x23 is a Yxe2x80x23xe2x80x94(CH2)nxe2x80x94 group, Zxe2x80x23 is CONR6, and Yxe2x80x23 is H, C6-C10 aryl, C3-C9 heteroaryl, morpholino, piperidino, pyrrolidino or isoindolyl. All of the other substituents are as previously defined.
In Scheme G, the compounds of structure (43) are prepared by coupling the free amine of structure (39) or the R6xe2x80x2-substituted amines of structure (40) with the acid of structure (42). Specifically, an acid of structure (42) is contacted with 1.2 to 1.7 equivalents of a suitable base, such as N-methylmorpholine, in a suitable solvent, such as tetrahydrofuran. The reaction mixture is cooled to a temperature of between xe2x88x9250xc2x0 C. and 0xc2x0 C. with xe2x88x9225xc2x0 C. to xe2x88x9220xc2x0 C. being preferred, before the addition of 1.2 to 1.7 equivalents of isobutyl chloroformate. The reaction is allowed to stir for 30 minutes to 3 hours to allow for the formation of the mixed anhydride, an activated intermediate. While maintaining the temperature at between xe2x88x9250xc2x0 C. and 0xc2x0 C., an appropriate free amine of structure (39) or an appropriate R6xe2x80x2-substituted amines of structure (40) is added. The reaction may, after the addition of amine of structures (39) or (40) is complete, be warmed to room temperature. The reaction requires from 2 to 48 hours. The product (43) can be isolated and purified by techniques well known in the art, such as extraction, evaporation, chromatography, and recrystallization.
Alternatively, for example, an acid of structure (42) is contacted with thionyl chloride or oxalyl chloride to provide an acid chloride intermediate. The reaction is carried out using thionyl chloride or oxalyl chloride as a solvent or the reaction can be carried out in a suitable solvent, such as toluene, benzene, dichloromethane, carbon tetrachloride, or chloroform. The reaction may be carried out in the presence of a suitable catalyst, such as dimethylformamide or pyridine. The reaction is carried out at temperatures of from xe2x88x9240xc2x0 C. to the refluxing temperature of the solvent. The reaction generally requires from 30 minutes to 24 hours. The acid chloride intermediate can isolated and purified by techniques well known in the art, such as evaporation, extraction, chromatography, and recrystallization.
The acid chloride intermediate is then contacted with an appropriate amine of structures (39) or (40). The reaction is carried out in a suitable solvent, such as toluene, tetrahydrofuran, dimethylformamide, dichloromethane, pyridine, or chloroform. The reaction is carried out in the presence of a slight molar excess of a suitable base, such as triethylamine, sodium carbonate, potassium bicarbonate, pyridine or diisopropylethyl amine. The reaction is carried out at a temperature of from xe2x88x9270xc2x0 C. to the refluxing temperature of the solvent. The reaction generally requires from 30 minutes to 24 hours. The product of structure (43) can be isolated and purified by techniques well known in the art, such as extraction, evaporation, chromatography, and recrystallization.
Alternatively, for example, an acid of structure (42) is contacted with a slight molar excess of an appropriate amine of structures (39) or (40) and 1-hydroxybenzotriazole hydrate in the presence of a slight molar excess of a coupling agent, such as dicyclohexylcarbodiimide (DCC) or 1-(3-dimethyaminopropyl)-3-ethylcarbodiimide (EDC). The reaction is carried out in the presence of a suitable base, such as diisopropylethyl amine. The reaction is carried out in a suitable solvent, such as dichloromethane or chloroform. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, chromatography, and recrystallization.
The compounds of structure (42), and activated intermediates thereof, are commercially available or may be readily prepared by techniques and procedures well known and appreciated by one of ordinary skill in the art. For example, benzoic acid, 1-naphthoic acid, 2-naphthoic acid, quinaldic acid, 4-pyridazine-carboxylic acid, 4-pyrazolecarboxylic acid, 2-furoic acid, 3-furoic acid, 2-pyrazinecarboxylic acid, 2-thiophenecarboxylic acid, 4-morpholinecarbonyl chloride, Boc-isonipecotic acid, isonicotinic acid, and picolinic acid are commercially available from Aldrich Chemical Co., Inc and Baychem, Inc.
The cis xcex1-thioamide of structure (15), the trans xcex1-thioamide of structure (16), and the xcex1-thioamide of structure (41) where R3 is a Qxe2x80x23xe2x80x94Zxe2x80x24xe2x80x94(CH2)mxe2x80x94 group, wherein Qxe2x80x23 is as defined in Scheme G, m is defined previously and Zxe2x80x24 is NHC(O)NR6, can be synthesized according to techniques well known and appreciated by one of ordinary skill in the art. A general synthetic scheme for preparing these compounds, signified as the compounds of structure (45), is set forth in Scheme H wherein all substituents, unless otherwise indicated, are previously defined. 
Scheme H provides a general synthetic procedure for preparing compounds of structures (15), (16) and (41) wherein R3 is a Qxe2x80x23xe2x80x94Zxe2x80x24xe2x80x94(CH2)mxe2x80x94 group, wherein Qxe2x80x23 is as defined in Scheme G, m is defined previously and Zxe2x80x24 is NHC(O)NR6. All of the other substituents are as defined above.
In Scheme H, the compounds of structure (45) are prepared by reacting a free amine of structure (39) or a R6xe2x80x2-substituted amine of structure (40) with the isocyanate of structure (44). For example, an equivalent of, or a slight molar excess of, an appropriate isocyanate of structure (44) is added to a solution of an appropriate free amine of structure (39) or an appropriate R6xe2x80x2-substituted amine of structure (40) in a suitable dry aromatic solvent, such as anhydrous benzene or anhydrous toluene. The mixture is then refluxed for a period of time ranging from 2-24 hours. The appropriate compound of structure (45) can be isolated and purified by techniques well known in the art, such as extraction, evaporation, chromatography, and recrystallization.
The compounds of structure (44), and activated intermediates thereof, are commercially available or may be readily prepared by techniques and procedures well known and appreciated by one of ordinary skill in the art. For example, phenyl isocyanate and 1-naphthyl isocyanate are available from Aldrich Chemical Co., Inc. Other compounds of structure (44) which are known in the art include 4-methyphenyl isocyanate, 4-methoxyphenyl isocyanate, 2-naphthyl isocyanate, 4-aminophenyl isocyanate, 4-fluorophenyl isocyanate, 3-chlorophenyl isocyanate, 4-chlorophenyl isocyanate, 3,4-dichlorophenyl isocyanate, 2,6-dimethylphenyl isocyanate, 2-methoxy-1-naphthyl isocyanate, 2,4,6-trimethylphenyl isocyanate and 4-nitrophenyl isocyanate.
The cis xcex1-thioamide of structure (15), the trans xcex1-thioamide of structure (16), and the xcex1-thioamide of structure (41) where R3 is a Q 3xe2x80x94Zxe2x80x25xe2x80x94(CH2)mxe2x80x94 group, wherein Qxe2x80x23 is as defined in Scheme G, m is defined previously and Zxe2x80x25 is OC(O)NR6, can be synthesized according to techniques well known and appreciated by one of ordinary skill in the art. A general synthetic scheme for preparing these compounds, signified as the compounds of structure (48), is set forth in Scheme I wherein all substituents, unless otherwise indicated, are previously defined. 
Scheme I provides a general synthetic procedure for preparing compounds of structures (15), (16) and (41) wherein R3 is a Qxe2x80x23xe2x80x94Zxe2x80x25xe2x80x94(CH2)mxe2x80x94 group, wherein Qxe2x80x23 is as defined in Scheme G, m is defined previously and Zxe2x80x25 is OC(O)NR6. All of the other substituents are as defined above.
In Scheme I, step a, an appropriate free amine of structure (39) or an appropriate R6xe2x80x2-substituted amine of structure (40) is coupled to the chloroformate of structure (46) in the presence of a suitable solvent, such as toluene, tetrahydrofuran, dimethylformamide, dichloromethane, pyridine, or chloroform. The reaction is carried out in the presence of a slight molar excess of a suitable base, such as triethylamine, sodium carbonate, potassium bicarbonate, pyridine or diisopropylethylamine. The reaction is carried out at a temperature of from xe2x88x9270xc2x0 C. to the refluxing temperature of the solvent. The reaction generally requires from 30 minutes to 24 hours. The product of structure (48) can be isolated and purified by techniques well known in the art, such as extraction, evaporation, chromatography, and recrystallization.
The chloroformates of structure (46) are commercially available or may be readily prepared by techniques and procedures well known and appreciated by one of ordinary skill in the art. For example, phenyl chloroformate, benzyl chloroformate, 4-chlorophenyl chloroformate, 4-nitrophenyl chloroformate, 4-methylphenyl chloroformate, 4-bromophenyl chloroformate, 4-fluorophenyl chloroformate, 4-methoxyphenyl chloroformate and chloroformic acid 2-naphthyl ester are available from Aldrich Chemical Co., Inc., or are otherwise known in the art.
Alternatively, in Scheme I, step a1, an appropriate free amine of structure (39) or an appropriate R6xe2x80x2-substituted amine of structure (40) is reacted with the anhydride of structure (47) according to the anhydride coupling procedure described previously in Scheme G.
The anhydrides of structure (47) may be readily prepared by techniques and procedures well known and appreciated by one of ordinary skill in the art. See for example, Pope, B. M. et al., Org. Synth., VI, 418 (1988); Dean, C. S. et al., Chem. Comm., 728 (1969); Tarbell, D. S. et al., Proc. Natl. Acad. Sci. (USA) 69, 730 (1972) or Dean, C. S. et al., J. Org. Chem. 35, 3393 (1970).
The cis xcex1-thioamide of structure (15), the trans xcex1-thioamide of structure (16), and the xcex1-thioamide of structure (41) where R3 is a Qxe2x80x23xe2x80x94Zxe2x80x25xe2x80x94(CH2)mxe2x80x94 group, wherein Qxe2x80x23 is as defined in Scheme G, m is defined previously and Zxe2x80x26 is SO2NR6, can be synthesized according to techniques well known and appreciated by one of ordinary skill in the art. A general synthetic scheme for preparing these compounds, signified as the compounds of structure (51), is set forth in Scheme J wherein all substituents, unless otherwise indicated, are previously defined. 
Scheme J provides a general synthetic procedure for preparing compounds of structures (15), (16) and (41) wherein R3 is a Qxe2x80x23xe2x80x94Zxe2x80x26xe2x80x94(CH2)mxe2x80x94 group, wherein Qxe2x80x23 is as defined in Scheme G, m is defined previously and Zxe2x80x26 is SO2NR6. All of the other substituents are as defined above.
In Scheme J, an appropriate free amine of structure (39) or an appropriate R6xe2x80x2-substituted amine of structure (40) is reacted with the with the chloride of structure (49) or the anhydride of structure (50) according to the anhydride coupling procedure described previously in Scheme G.
The chlorides of structure (49) are commercially available or may be readily prepared by techniques and procedures well known and appreciated by one of ordinary skill in the art. For example, benzenesulfonyl chloride, 1-napthalenesulfonyl chloride, 2-napthalenesulfonyl chloride, dansyl chloride, 8-quinolinesulfonyl chloride, 2-dibenzofuransulfonyl chloride, 1,2-napthoquinone-2-diazide-4-sulfonyl chloride, N-morpholinylsulfonyl chloride, N-piperidinylsulfonyl chloride, 2,4,5-trichlorobenzenesulfonyl chloride, 2,5-dichlorobenzenesulfonyl chloride, 2-nitrobenzenesulfonyl chloride, 2,4-dinitrobenzenesulfonyl chloride, 3,5-dichloro-2-hydroxybenzenesulfonyl chloride, 2,4,6-triisopropylbenzenesulfonyl chloride, 2-mesitylenesulfonyl chloride, 3-nitrobenzenesulfonyl chloride, 4-bromobenzenesulfonyl chloride, 4-fluorobenzenesulfonyl chloride, 4-chlorobenzenesulfonyl chloride, 4-chloro-3-nitrobenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride, 4-methoxybenzenesulfonyl chloride, 4-t-butylbenzenesulfonyl chloride, p-toluenesulfonyl chloride, 2,3,4-trichlorobenzenesulfonyl chloride, 2,5-dimethoxybenzenesulfonyl chloride, 4-ethylbenzenesulfonyl chloride, 3,4-dimethoxybenzenesulfonyl chloride, 2,6-dichlorobenzenesulfonyl chloride, 3-bromobenzenesulfonyl chloride, 4-methoxy-2-nitrobenzenesulfonyl chloride and 4-n-butylbenzenesulfonyl chloride are available from Aldrich Chemical Co., Inc., other chemical suppliers, such as Lancaster, Salor, or Maybridge, or are otherwise known in the art.
The anhydrides of structure (50) are commercially available or may be readily prepared by techniques and procedures well known and appreciated by one of ordinary skill in the art. For example, benzenesulfonic anhydride, 4-toluenesulfonic anhydride, 2-mesitylenesulfonic anhydride and 4-nitrobenzenesulfonic anhydride are available from Aldrich Chemical Co., Inc., or are otherwise known in the art.
The cis xcex1-thioamide of structure (15), the trans o-thioamide of structure (16), and the xcex1-thioamide of structure (41) where R3 is a Qxe2x80x23xe2x80x94Zxe2x80x27xe2x80x94(CH2)mxe2x80x94 group, wherein Qxe2x80x23 is as defined in Scheme G, m is defined previously and Zxe2x80x27 is NR6C(O), can be synthesized according to techniques well known and appreciated by one of ordinary skill in the art. A general synthetic scheme for preparing these compounds, signified as the compounds of structure (54), is set forth in Scheme K wherein all substituents, unless otherwise indicated, are previously defined. 
Scheme K provides a general synthetic procedure for preparing compounds of structures (15), (16) and (41) wherein R3 is a Qxe2x80x23xe2x80x94Zxe2x80x27xe2x80x94(CH2)mxe2x80x94 group, wherein Qxe2x80x23 is as defined in Scheme G, m is defined previously and Zxe2x80x27 is NR6C(O). All of the other substituents are as defined above.
In Scheme K, step a, an appropriate ester of structure (52) is deprotected under conditions well known in the art to provide the acid of structure (53). For example, when R6xe2x80x2 is methyl or ethyl, the ester of structure (52) is dissolved in a suitable organic solvent, such as ethanol and treated with approximately an equal volume of water. To this solution, with stirring is added 1 to 2 equivalents of lithium hydroxide and the reaction is allowed to stir for 1 to 6 hours. The resulting acid is then isolated and purified by techniques well known in the art. For example, the organic solvent is removed under vacuum and the remaining aqueous solution is acidified with dilute hydrochloric acid. The aqueous phase is then extracted with a suitable organic solvent, such as ethyl acetate, and the combined organic extracts are dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue can then be purified by flash chromatography on silica gel with a suitable eluent, such as methanol/chloroform to provide the acid of structure (53).
In Scheme K, step b, the acid of structure (53) is coupled with the amine of structure (53a) under conditions well known in the art to provide the retroamide of structure (54). For example, the acid of structure (53) is dissolved in a suitable organic solvent, such as methylene chloride, under an inert atmosphere, such as nitrogen. The solution is then treated with one to four equivalents of a suitable amine, such as N-methylmorpholine, cooled to about xe2x88x9220xc2x0 C. and one equivalent of isobutylchloroformate is added. The reaction is allowed to stir for about 10 to 30 minutes and 1 to 4 equivalents of the amine of structure (53a) is added to the reaction. The reaction is stirred for 30 minutes to 2 hours at about xe2x88x9220xc2x0 C. and then it is allowed to warm to room temperature and stir for 1 to 3 hours. The retroamide (54) is then isolated and purified by techniques well known in the art, such as extractive techniques and flash chromatography. For example, the reaction is diluted with a suitable organic solvent such as methylene chloride, rinsed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue is purified by flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexane to provide the retroamide (54).
Alternatively, the amine of structure (53a) is dissolved in a suitable anhydrous organic solvent, such as methylene chloride under an inert atmosphere, such as nitrogen. To this solution is added an equivalent of N-hydroxybenztriazole hydrate, an equivalent of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and an equivalent of the acid of structure (53), dissolved in a suitable anhydrous organic solvent, such as methylene chloride. The reaction is then allowed to stir for about 1 to 15 hours. The retroamide of structure (54) is then isolated and purified by techniques well known in the art, such as extractive techniques and flash chromatography. For example, the reaction is diluted with a suitable organic solvent, such as ethyl acetate, rinsed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue is purified by flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexane to provide the retroamide (54).
The cis xcex1-thioamide of structure (15), the trans xcex1-thioamide of structure (16), and the xcex1-thioamide of structure (41) where R3 is a Qxe2x80x23xe2x80x94Zxe2x80x28xe2x80x94(CH2)mxe2x80x94 group, wherein Qxe2x80x23 is as defined in Scheme G, m is defined previously and Zxe2x80x28 is HNC(O)O, can be synthesized according to techniques well known and appreciated by one of ordinary skill in the art. A general synthetic scheme for preparing these compounds, signified as the compounds of structure (56), is set forth in Scheme L wherein all substituents, unless otherwise indicated, are previously defined. 
Scheme L provides a general synthetic procedure for preparing compounds of structures (15), (16) and (41) wherein R3 is a Qxe2x80x23xe2x80x94Zxe2x80x28xe2x80x94(CH2)mxe2x80x94 group, wherein Qxe2x80x23 is as defined in Scheme G, m is defined previously and Zxe2x80x28 is HNC(O)O. All of the other substituents are as defined above.
In Scheme L, step a, an appropriate ester of structure (52) is reduced under conditions well known in the art to provide the alcohol of structure (55). For example, the ester of structure (52) is dissolved in a suitable solvent, such as hexane, dichloromethane, tetrahydrofuran or toluene, with tetrahydrofuran being preferred, and contacted with a suitable reducing agent, such as lithium borohydride, sodium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, 9-borabicyclo[3.3.1]nonane, preferably lithium borohydride. The reaction is carried out by either adding a solution of an appropriate ester (52) to a solution of an appropriate reducing agent or by adding a solution of an appropriate reducing agent to a solution of an appropriate ester of structure (52). The addition is carried out at a temperature of from about xe2x88x9230xc2x0 C. to about 10xc2x0 C. The reaction is carried out at a temperature of from about 0xc2x0 C. to about 30xc2x0 C. The reaction generally requires from 2 to 5 hours. The product can be isolated by quenching and extraction. The quench is carried out at a temperature of from about xe2x88x9215xc2x0 C. to about 0xc2x0 C. The alcohol of structure (55) can be isolated by methods well known and appreciated in the art, such as extraction and evaporation. The alcohol of structure (55) can be purified as is well known in the art by chromatography and distillation.
In Scheme L, step b, the alcohol of structure (55) is reacted with the isocyanate of structure (44) according to the procedures set forth in Scheme H above to afford the appropriate compound of structure (56).
Alternatively, the cis xcex1-thioamide of structure (15), the trans xcex1-thioamide of structure (16), and the xcex1-thioamide of structure (41) can be synthesized according to techniques well known and appreciated by one of ordinary skill in the art. An alternate general synthetic scheme for preparing these compounds is set forth in Scheme M wherein all substituents, unless otherwise indicated, are previously defined. 
Scheme M provides an alternate general synthetic procedure for preparing compounds of structures (15), (16) and (41). All of the substituents are as defined above.
In Scheme M, step a, the thiol of structure (57a) in a suitable organic solvent such as dimethylformamide, is degassed and treated with ethyl bromoacetate (57b) and a suitable tertiary amine such as diisopropylethylamine. The reaction mixture is placed in a cooling bath and stirred for a period of time ranging from about 20 minutes to about 1 hour whereupon a precipitate is observed. The cooling bath is then removed and the reaction mixture is stirred for an additional 48 to 72 hours. The sulfide ester of structure (57) can be isolated by methods well known and appreciated in the art, such as extraction and evaporation. The sulfide ester of structure (57) can be purified as is well known in the art by chromatography and distillation.
In Scheme M, step b, the sulfide ester of structure (57) in a suitable organic solvent such as tetrahydrofuran is treated with an amide base such as lithium bis(trimethylsilyl)amide. The resulting intermediate is then reacted with an R3-substituted alkyl halide (R3CH2-Hal) to yield the R3-substituted sulfide ester of structure (58). The R1-substituted sulfide ester of structure (58) can be isolated by methods well known and appreciated in the art, such as extraction and evaporation. The R3-substituted sulfide ester of structure (58) can be purified as is well known in the art by chromatography and distillation.
In Scheme M, step c, the R3-substituted sulfide ester of structure (58) is deprotected to yield the R1-substituted sulfide acid of structure (59) according tothe procedure described in Scheme K, step a.
In Scheme M, step d, the R3-substituted sulfide acid of structure (59) is coupled with an appropriate compound of structures (11), (12) or (29) to provide an appropriate compound of structures (15), (16) or (41) according the procedures described in Scheme G.
The compounds of formula (1) wherein R4 is a xe2x80x94C(O)xe2x80x94(CH2)qxe2x80x94K group can be synthesized according to techniques well known and appreciated by one of ordinary skill in the art, as disclosed in U.S. Pat. No. 5,424,425, issued Jun. 13, 1995. A general synthetic scheme for preparing these compounds, signified as the compounds of structure (61), is set forth in Scheme N wherein all substituents, unless otherwise indicated, are previously defined. 
Scheme N provides a general synthetic procedure for preparing compounds of structure (61) wherein Kxe2x80x2 is 
R7xe2x80x3 represents Boc, C1-C4 alkyl or a xe2x80x94(CH2)pxe2x80x94Ar2 group. All of the other substituents are as defined above.
In Scheme N the appropriate thioacetyl compound of structure (61) can be prepared by reacting the appropriate bromoamide of structure (13), (14) or (30) with the appropriate triphenylmethyl aminothiolacetate of structure (60 or 60a) under basic conditions such as sodium hydride, hydrogen sulfide in a suitable aprotic solvent such as dimethylformamide.
For those thioacetyl compounds of structure (61) wherein Kxe2x80x2 is 
wherein R7xe2x80x2 is Boc, the Boc protecting group can be removed using trifluoroacetic acid to give the corresponding compounds where R7 is hydrogen.
In addition, the sulfide functionality of those thioacetyl compounds of structure (61) wherein Kxe2x80x2 is 
may be oxidized by techniques and procedures well known in the art, such as magnesium monoperoxyphthalic acid hexahydrate to give the thioacetyl compounds of structure (61) wherein K is 
wherein pxe2x80x2 is 1 or 2.
Scheme O provides a general synthetic scheme for preparing the triphenylmethyl aminothiolacetates of structures (60) and (60a). 
Scheme O provides a general synthetic procedure for preparing compounds of structure (64) and (64a) wherein Kxe2x80x3 is 
R7xe2x80x3 represents Boc, C1-C4 alkyl or a xe2x80x94(CH2)pxe2x80x94Ar2 group. All of the other substituents are as defined above.
In Scheme O, step a, a triphenylmercaptan (62) and bromoacetyl bromide (63) are reacted under basic conditions, such as pyridine, in an aprotic solvent, such as methylene chloride to give triphenylmethylbromothiolacetate of structure (64).
In Scheme O, step b, triphenylmethyl bromothiolacetate of structure (64) is reacted with the appropriate amino compound of structure (65) under basic conditions, such as pyridine, in an aprotic solvent such as methylene chloride to give the appropriate triphenylmethyl aminothiolacetate compound of structure (66).
In Scheme O, optional step c, the sulfide functionality of those thioacetyl compounds of structure (66) wherein Kxe2x80x3 is 
may be oxidized by techniques and procedures well known in the art, such as magnesium monoperoxyphthalic acid hexahydrate to give the thioacetyl compounds of structure (66a) wherein K is 
wherein pxe2x80x2 is 1 or 2.
Alternatively, the compounds of formula (1) wherein R4 is a xe2x80x94C(O)xe2x80x94(CH2)qxe2x80x94K group may be prepared as described in Scheme P. In Scheme P, all substituents are as previously defined unless otherwise indicated. 
Scheme P provides a general synthetic procedure for preparing compounds of structure (61) wherein all of the substituents are as previously defined.
In Scheme P, the thiol functionality of the thiol compounds of structures (17), (18) or (32) is coupled with the appropriate acid of structure (68) in the presence of a suitable coupling agent to give the appropriate thioacetyl compound of structure (61). For example, the appropriate thiol compound of structures structures (17), (18) or (32) can be reacted with the appropriate acid of structure (68) in the presence of a coupling agent such as 2-fluoro-1-methylpyridinium p-toluenesulfate, EDC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride), carbonyldiimidazole, EEDQ (1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, DCC, or diethylcyanophosphonate in a suitable aprotic solvent such as methylene chloride to give the appropriate thioacetyl compound of structure (61).
The compounds of formula (1) wherein R4 is a xe2x80x94Sxe2x80x94G group can be synthesized according to techniques well known and appreciated by one of ordinary skill in the art, as disclosed in PCT Int. Publ. No. WO 95/21839, published Aug. 17, 1995. A general synthetic scheme for preparing these compounds, signified as the compounds of structure (71), is set forth in Scheme Q wherein all substituents, unless otherwise indicated, are previously defined. 
The disulfides of structure (69) can be obtained by methods Inown in the art or by methods known analogously in the art, Roques, B. P. et al., J. Med. Chem. 33, 2473-2481 (1992).
In Scheme Q, an appropriate disulfide of structure (69) is contacted with an appropriate thiol of structures (17), (18) or (32) to give a disulfide of structure (70) or a protected form thereof. An appropriate disulfide of structure (70) is one in which G is as desired in the final product of formula (1) or gives rise upon deprotection to G as is desired in the final product of formula (1).
For example, an appropriate disulfide of structure (69) is contacted with an appropriate thiol of structures (17), (18) or (32). The reaction is carried out in a suitable solvent, such as ethanol, methanol, dichloromethane, or mixtures of ethanol or methanol and dichloromethane. The solvent is degassed by passing a stream of nitrogen gas through it for 15 minutes before the reaction is carried out. The reaction is carried out using from 1.0 to 4.0 molar equivalents of an appropriate compound of structure (69). The reaction is carried out at temperatures of from 0xc2x0 C. to the refluxing temperature of the solvent, with a temperature of 10xc2x0 C. to 30xc2x0 C. being preferred. The reaction generally requires from 1 to 48 hours. The product can be isolated by techniques well known in the art, such as extraction, evaporation, and precipitation. The appropriate disulfide or protected disulfide of structure (70) can be purified by chromatography and recrystallization.
The protected disulfides of structure (70) can be deprotected according to techniques well known in the art. The selection, use and removal of protecting groups and the removal of protecting groups in a sequential manner utilizing suitable protecting groups such as those described in Protecting Groups in Organic Synthesis by T. Greene is well known and appreciated by those skilled in the art.